Mechanisms of expression of pyruvate dehydrogenase deficiency caused by an E1alpha subunit mutation

OBJECTIVE: To characterize the biochemical mechanisms of expression of the pyruvate dehydrogenase (PDH) E1alpha subunit exon 10 R302C missense mutation. BACKGROUND: Mutations in the X-linked E1alpha subunit gene are responsible for most cases of PDH deficiency, an important cause of neurodevelopmental defects and neurodegeneration with primary lactic acidemia. Although the disease shows extreme allelic heterogeneity, the R302C mutation has been defined in several unrelated cases. METHODS: Cell lines expressing selectively either the mutant or wild-type E1alpha alleles against identical genetic backgrounds were generated from the fibroblasts of a female heterozygous for the R302C mutation. Enzyme activity, mRNA, polypeptide expression, and turnover were studied in each. RESULTS: The residual PDH activity was below measurable levels in the cell line (B5) expressing only the mutant allele and normal in the wild-type polypeptide expressing (A10) cell line, confirming that the R302C mutation alone is sufficient to cause a severe PDH deficiency. The mutant polypeptide was less stable than the wild-type polypeptide, but the steady-state level of the mutant E1alpha protein was reduced only two- to threefold. CONCLUSIONS: The primary mechanism of expression of the R302C mutation must be limitation of catalytic efficiency. We speculate that catalysis may be inhibited in the mutant polypeptide because conformational changes are induced near serine 300, a residue that is particularly important as a regulatory phosphorylation site in the wild-type polypeptide.     

Surgical treatment of cyclosporine A- and nifedipine-induced gingival enlargement: gingivectomy versus periodontal flap

The purpose of this study was to compare probing depth resolution achieved by gingivectomy and periodontal flap techniques in the treatment of cyclosporine A- and nifedipine-induced gingival enlargement. Ten kidney transplant patients who were receiving cyclosporine A and nifedipine for at least 6 months participated in the study. Five patients were randomly assigned to the gingivectomy group and 5 patients to the periodontal flap group. Only anterior segments of the oral cavity (canine to canine) were surgically treated. Clinical measurements, including probing depths, plaque index, and gingival sulcus index, were taken at baseline, 6 weeks, 6 months, and 1 year. Results showed that probing depths, while similar for both groups in the first 6 weeks of the study, were significantly shallower for the periodontal flap group when compared to the gingivectomy group at 6 months (2.48 +/- 0.34 mm versus 4.87 +/- 0.79 mm, respectively) and 1 year (322 +/- 0.65 mm versus 6.40 +/- 1.02 mm, respectively). Within its limitations, this study suggests that the pocket reduction achieved by the periodontal flap may be sustained for longer periods of time than by the gingivectomy technique in the treatment of cyclosporine A- and nifedipine-induced gingival enlargement.     

In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogenous leukemia in first complete remission

PURPOSE: To evaluate in a prospective study the efficacy of autologous bone marrow transplantation (BMT) in adult patients with acute myelogenous leukemia (AML) in first remission, using a single course of high-dose Cytarabine (HD Ara-C) consolidation therapy as in vivo purging. PATIENTS AND METHODS: Sixty consecutive adult patients with AML in first complete remission (CR) were treated with HD Ara-C consolidation therapy as a method of in vivo purging before marrow collection. High-dose therapy consisted of fractionated total-body irradiation (FTBI) 12 Gy, intravenous etoposide 60 mg/kg, and cyclophosphamide 75 mg/kg, followed by reinfusion of cryopreserved marrow. RESULTS: Sixty patients underwent consolidation treatment with HD Ara-C with the intent to treat with autologous BMT. Sixteen patients were unable to proceed to autologous BMT (10 patients relapsed, one died of sepsis, one developed cerebellar toxicity, two had inadequate blood counts, and two refused). Forty-four patients underwent autologous BMT and have a median follow-up time of 37 months (range, 14.7 to 68.7) for patients who are alive with no relapse. The cumulative probability of disease-free survival (DFS) at 24 months in the intent-to-treat group is 49% (95% confidence interval [CI], 37% to 62%) and in those who actually underwent autologous BMT is 61% (95% CI, 46% to 74%). The probability of relapse was 44% (95% CI, 31% to 58%) and 33% (95% CI, 20% to 49%) for the intent-to-treat and autologous BMT patients, respectively. CONCLUSION: This approach offers a relatively high DFS rate to adult patients with AML in first CR. The results of this study are similar to those achieved with allogeneic BMT.     

Noninvasive measurement of distal radius instability

Except for subjective clinical criteria, there is no formal definition of distal radius fracture instability in the literature. The purposes of this ex vivo biomechanical study were (1) to provide an objective mechanical definition of fracture instability and (2) to demonstrate a noninvasive method that allows for direct measurement of instability. The following 3 questions are addressed: (1) Can the stability of distal radius fractures be measured using computed tomography (CT)? (2) Are the stability measurements reproducible? (3) How does external fixation change stability? A CT technique is described that was used to measure displacement of fracture fragments and measure the compliance of ex vivo distal radius fractures before and after external fixation. Validation studies of the CT technique revealed a mean coefficient of variation of 0.38. There was a linear relationship between measured and known displacements for all 3 orthogonal planes (coefficient of determination 0.99; p < .01). There was significant fracture displacement with loads as small as 20 N. The slope of the load-displacement curve (structural compliance) provided a quantitative measure of fracture instability. Fracture compliance decreased up to 69% after application of an external fixator.     

Subcell treatment of 90° metal corners in FDTD

A simple extension to the staircase FDTD algorithm yielding accurate subcell models of flat metal walls and corners is presented. Electric field nodes on the edges of staircase models of perfect electric conductors are replaced by values obtained using interpolation or analytic continuation into the metal. The algorithm is validated by computing the resonant frequencies of cavities     

Strength and electrical conductivity of deformation-processed Cu-15 Vol Pct Fe alloys produced by powder metallurgy techniques

Powder metallurgical techniques have been employed to prepare the precursor billets in the preparation of Cu-15 vol pct Fe alloys by deformation processing. It has been demonstrated that by (1) using high-purity gas-atomized Cu powders blended with commercial high-purity Fe powders and (2) controlling the time/temperature processing conditions within specific limits, it is possible to produce Cu-Fe deformation-processed alloys with strength/conductivity properties matching those of Cu-Nb, Cu-Ta, and Cu-Cr alloys. These properties are significantly superior to the best commercial alloys. formerly with the Department of Materials Science and Engineering and Ames Laboratory, Iowa State University This article is based on a presentation made in the symposium “High Performance Copper-Base Materials” as part of the 1991 TMS Annual Meeting, February 17–21, 1991, New Orleans, LA, under the auspices of the TMS Structural Materials Committee.     

Aortopulmonary fistula in an infected Dacron graft for coarctation of the aorta: an uncommon cause of hemoptysis

Hemoptysis secondary to an aortobronchial fistula is rare and uniformly fatal when left untreated. The authors describe a case of massive hemoptysis caused by an aortopulmonary fistula in an infected Dacron graft used successfully to repair a coarctation of the aorta.